title: Minor splicing pathway is not minor any more: implications for the pathogenesis of motor neuron diseases.
abstract: To explore the molecular pathogenesis of amyotrophic lateral sclerosis (ALS), the nuclear function of TAR-DNA binding protein 43 kDa (TDP-43) must be elucidated. TDP-43 is a nuclear protein that colocalizes with Cajal body or Gem in cultured cells. Several recent studies have reported that the decreasing number of Gems accompanied the depletion of the causative genes for ALS, TDP-43 and FUS. Gems play an important role in the pathogenesis of spinal muscular atrophy. Gems are the sites of the maturation of spliceosomes, which are composed of uridylate-rich (U) snRNAs (small nuclear RNAs) and protein complex, small nuclear ribonuclearprotein (snRNP). Spliceosomes regulate the splicing of pre-mRNA and are classified into the major or minor classes, according to the consensus sequence of acceptor and donor sites of pre-mRNA splicing. Although the major class of spliceosomes regulates most pre-mRNA splicing, minor spliceosomes also play an important role in regulating the splicing or global speed of pre-mRNA processing. A mouse model of spinal muscular atrophy, in which the number of Gems is decreased, shows fewer subsets U snRNAs. Interestingly, in the central nervous system, U snRNAs belonging to the minor spliceosomes are markedly reduced. In ALS, the U12 snRNA is decreased only in the tissue affected by ALS and not in other tissues. Although the molecular mechanisms underlying the decreased U12 snRNA resulting in cell dysfunction and cell death in motor neuron diseases remain unclear, these findings suggest that the disturbance of nuclear bodies and minor splicing may underlie the common molecular pathogenesis of motor neuron diseases.
authors.affiliation: Department of Molecular Neuroscience, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ishihara
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiga
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ariizumi
authors.forename: Akio
authors.initials: A
authors.lastname: Yokoseki
authors.forename: Masatoyo
authors.initials: M
authors.lastname: Nishizawa
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000378:metabolism*; D055531:Gemini of Coiled Bodies / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D016472:Motor Neuron Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000378:metabolism; D012326:RNA Splicing
chemical_list: D004268:DNA-Binding Proteins; D012313:RNA
keywords: RNA splicing; U12 small nuclear RNA; amyotrophic lateral sclerosis; gemini of coiled bodies; spliceosomes